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BET bromodomain inhibition of MYC-amplified medulloblastoma
Pratiti Bandopadhayay1, Guillaume Bergthold, Brian Nguyen
1Authors' Affiliations: Departments of Cancer Biology and Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School; Pediatric Neuro-Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Pediatric Hematology/Oncology, Boston Children's Hospital; Center for Cancer Genome Characterization, Dana-Farber Cancer Institute, Boston; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Departments of Neurology and Neurological Sciences and Neurosurgery, Stanford University School of Medicine; Stanford Cancer Institute, Stanford University Medical Center, Stanford; Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla; Department of Neurology, Pediatrics, and Neurosurgery, University of California, San Francisco, California; and Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
Purpose:
MYC-amplified medulloblastomas are highly lethal tumors. Bromodomain and extraterminal (BET) bromodomain inhibition has recently been shown to suppress MYC-associated transcriptional activity in other cancers. The compound JQ1 inhibits BET bromodomain-containing proteins, including BRD4. Here, we investigate BET bromodomain targeting for the treatment of MYC-amplified medulloblastoma.
Experimental Design:
We evaluated the effects of genetic and pharmacologic inhibition of BET bromodomains on proliferation, cell cycle, and apoptosis in established and newly generated patient- and genetically engineered mouse model (GEMM)-derived medulloblastoma cell lines and xenografts that harbored amplifications of MYC or MYCN. We also assessed the effect of JQ1 on MYC expression and global MYC-associated transcriptional activity. We assessed the in vivo efficacy of JQ1 in orthotopic xenografts established in immunocompromised mice.
Results:
Treatment of MYC-amplified medulloblastoma cells with JQ1 decreased cell viability associated with arrest at G1 and apoptosis. We observed downregulation of MYC expression and confirmed the inhibition of MYC-associated transcriptional targets. The exogenous expression of MYC from a retroviral promoter reduced the effect of JQ1 on cell viability, suggesting that attenuated levels of MYC contribute to the functional effects of JQ1. JQ1 significantly prolonged the survival of orthotopic xenograft models of MYC-amplified medulloblastoma (P < 0.001). Xenografts harvested from mice after five doses of JQ1 had reduced the expression of MYC mRNA and a reduced proliferative index.
Conclusion:
JQ1 suppresses MYC expression and MYC-associated transcriptional activity in medulloblastomas, resulting in an overall decrease in medulloblastoma cell viability. These preclinical findings highlight the promise of BET bromodomain inhibitors as novel agents for MYC-amplified medulloblastoma.
Insights
Bromodomain and extraterminal (BET) bromodomain inhibition with JQ1 effectively suppressed MYC-amplified medulloblastomas. This targeted therapy reduced tumor cell viability and prolonged survival in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- MYC-amplified medulloblastomas are aggressive and lethal pediatric brain tumors.
- Bromodomain and extraterminal (BET) bromodomain inhibition is a potential therapeutic strategy.
- JQ1 is a known inhibitor of BET proteins, including BRD4.
Purpose of the Study:
- To investigate the efficacy of BET bromodomain inhibition targeting MYC-amplified medulloblastoma.
- To evaluate the effects of JQ1 on MYC expression and associated transcriptional activity.
Main Methods:
- Assessed the impact of genetic and pharmacologic BET bromodomain inhibition on medulloblastoma cell lines and xenografts.
- Utilized patient-derived and genetically engineered mouse models (GEMMs) with MYC or MYCN amplification.
- Evaluated in vivo efficacy of JQ1 in orthotopic xenograft models.
Main Results:
- JQ1 treatment decreased medulloblastoma cell viability, induced G1 arrest, and promoted apoptosis.
- Downregulation of MYC expression and its transcriptional targets was observed.
- Exogenous MYC expression partially rescued JQ1's effects, confirming MYC's role.
- JQ1 significantly prolonged survival in orthotopic xenograft models (P < 0.001).
Conclusions:
- JQ1 effectively suppresses MYC expression and transcriptional activity in medulloblastomas.
- BET bromodomain inhibition shows promise as a novel therapeutic approach for MYC-amplified medulloblastoma.
- These preclinical findings support further development of BET inhibitors for this aggressive cancer.
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